Substituted 1H-benzo[d]imidazol-2(3H)-ones (A) are heterocyclic compounds which belong to the happy few class of “privileged” structures.

Privileged structures are defined as “molecular frameworks which are able of providing useful ligands for more than one type of receptor or enzyme target by judicious structural modifications”. (Duarte, Carolina D.; Barreiro, Eliezer J.; Fraga, Carlos A. M., Mini-Reviews in Medicinal Chemistry (2007), 7(11), 1108-1119. “Privileged structures and analogue-based drug discovery” Kubinyi, Hugo. In Analogue-Based Drug Discovery (2006), 53-68. Editor(s): Fischer, Janos; Ganellin, C. Robin. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany).
The status of privileged structure results from the outstanding number of application of this framework in various type of receptors or enzyme targets. More than 8000 differently substituted 1H-benzo[d]imidazol-2(3H)-ones have been associated with biological application in the chemical and patent literature according to the Chemical Abstracts.
The interest in new derivatives and new applications is still vivid as exemplified in recent patent application such as WO 2008065508 for treatment of obesity, WO 2007-US80831 describing the use of domperidone for reducing analgesics adverse effect, WO 2008070150 for treating hyper-proliferative disorders and diseases associated with angiogenesis, WO 2008070264 describing a nasal spray composition comprising antihistamine, anti-inflammatory agent and decongestant for treating rhinitis and/or sinusitis, WO 2008061968 for benzimidazolone derivatives displaying affinity for the 5-HT2B-receptor in the treatment of pulmonary arterial hypertension, WO 2008051533 for the preparation of benzimidazole derivatives as CRF receptor antagonists, WO 2008013925 for fungicidal azocyclic amides, WO 2008032164 for benzimidazolone derivatives and their preparation, pharmaceutical compositions and use in the treatment of CB1 and CB2 receptor mediated diseases.
The status of privileged structure and the need of the optimization of the substitution pattern impelled the development of libraries of benzimidazolones in several pharmaceutical companies.
The preparation of libraries of 1H-benzo[d]imidazol-2(3H)-one derivatives rests on the discovery of highly efficient and regioselective synthetic methods for the preparation of the 1H-benzo[d]imidazol-2(3H)-one differently substituted on the N1 and N3 nitrogen atom. (Zou, B.; Yuan, Q.; Ma, D. Organic Lett., 2007, 9(21), 4291-4294. Xu, X-J.; Zong, Y-X. Tetrahedron Lett. 2007, 48, 129-132. McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3311-3314 and reference therein).
Among the thousands of N1,N3 disubstituted 1H-benzo[d]imidazol-2(3H)-ones, those presenting an N-alkenyl substituent such as compound of formula (B), occupy a special position since the alkenyl group can be considered as a protecting group which can be hydrolyzed to yield regioselectively R2-substituted 1H-benzo[d]imidazol-2(3H)-ones.

The synthesis of these compounds B starts from the 1,2-diaminobenzene which is reacted on a beta ketoester according to Scheme A.

In this process several by-products have been identified which decrease severely the reaction yield. (Kuethe, J. T.; Varon, J.; Childers, K. G. Tetrahedron 2007, 63, 11489-11502 and references therein). Recently, spirobenzimidazolines were shown to rearrange in basic medium and triphosgene to yield N-alkenyl-benzimidazolinones (X═O, S, NR) (Kuethe, J. T.; Varon, J.; Childers, K. G. Tetrahedron 2007, 63, 11489-11502).
